Projects

Project: Development of cell therapy after SCI

Project manager: Anna O'Sullivan

Paralysis following spinal cord injury (SCI) is probably one of the most drastic changes in life that can occur after an accident or disease. Unfortunately, no curative therapy is currently available against SCI-related functional loss and therefore new strategies for treatment of SCI urgently need to be developed.

Following SCI, the final dysfunction not only results from the initial destruction of tissue, but also successive inflammation, demyelination of the axons and glial scar formation. Together, these events prevent the regenerative outgrowth of lesioned axons and therefore a regain of lost functions. The reconstitution of myelin within the spinal cord and guidance through the glial scar would help the axons to rebuild the connection with their targets.

We investigate how cell therapy could support this objective. A promising candidate for this task is the so-called Olfactory Ensheathing Cell (OEC). OECs are easily accessible, can be expanded in vitro and could therefore be used for autologous transplantation. OECs constitute a unique cell type exclusively found in the olfactory system.

In contrast to the other two myelinating cell types (Schwann cells and oligodendrocytes), OECs have the ability to accompany axons from the peripheral into the central nervous system. Accumulating evidence supports the positive effects of transplanted OECs on regeneration following SCI. Our aim is to maximize the regenerative potential of neural tissue with the involvement of cell therapy, such as application of OECs.

Glial cells in culture: Oligodendrocytes (red) and astrocytes (green)

Project: Adult neurogenesis

Project manager: Lara Bieler

Adult neurogenesis is the process of generating new neurons in the adult organism. This occurs mainly in two regions of the brain: in the dentate gyrus of the hippocampus and in the subventricular zone of the third ventricle. Adult neurogenesis can be regulated by many different intrinsic and extrinsic factors. Ageing, neurodegenerative diseases and traumatic injuries are often associated with a loss of neurons, which functions cannot be regenerated at the current state of medical science.

Flavonoids, a class of secondary plant metabolites, have several positive effects on the human organism. A recent study demonstrated that a flavonoid-rich diet can reduce the cognitive decline observed in Alzheimer`s disease[1]. Moreover, certain flavonoids were shown to have antidepressant [2] and anxiolytic activities in animal experiments [3].

Humulus lupulus L., also known as common hop, is a plant with a very high content of flavonoids. In different in vitro experiments, performed in our laboratory, we demonstrated that the treatment of neural stem cell cultures with specific hops-derived flavonoids enhanced the neuronal differentiation,. Moreover, these flavonoids increased outgrowth and branching of neurites and act neuroprotective [4]. Therefore the pharmacological effects of these flavonoids on the central nervous system is being further investigated in vivo.

Insults to the spinal cord are devastating conditions and lead to lifelong issues for affected individuals.

The pathophysiology of spinal cord injury (SCI) can be seen as an event that develops over two distinct phases. The first one is the primary hit per se, that leads to cell disruption, petechial bleeding and cell death. The hemorrhage and the cellular debris in the spinal cord initiate a multi-faceted cascade of secondary events including ischemia, excitotoxicity, edema and a strong inflammatory response. Thereafter a scar accompanied by a pseudocyst can arise according to the injury severity . This tissue response is on one hand beneficial to embank the ongoing pathological reaction to the lesion site and thereby prevent further damage to the surrounding tissue. It constitutes however on the other hand an enormous physical obstacle for spontaneous neuroregeneration.

We are studying the pathophysiological cascade of SCI, especially with regard to aging and inflammation in order to modulate the micromilieu of the injured spinal cord and to promote regeneration. Knowledge obtained from these investigations on pre-clinical models of SCI will be further implemented in the development of cell transplantation strategies. A big hurdle for transplanted cells is the local inhospitable environment for the differentiation and integration of neuronal and oligodendroglial cells. Recent in vitro results showed that specific factors could efficiently prime neural progenitor cells towards neuronal or oligodendroglial cell fates. The potential of cell priming prior to transplantation is being addressed in pre-clinical models of SCI.

Project: Characterization of ectopic immature neurons in the brain

Project manager: Pete Rotheneichner

Adult neurogenesis, the generation of new neurons in the adult brain, takes place in two distinct areas. In the so called neurogenic niches, namely the gyrus dentatus of the hippocampus and the subventricular zone of the lateral ventricles, stem- and progenitor cells divide and mature to functional neurons.

Interestingly it was recently shown, that some cells dispersed throughout the central nervous system share similar characteristics with the neurogenic niche cells, for example the expression of the protein Doublecortin - a marker for neuronal progenitors. These ectopic cells, however, seem to be in a quiescent state. We have generated a transgenic mouse model, where a fluorescent reporter driven by the Doublecortin-promoter can be induced upon administration of Tamoxifen. This procedure results in the permanent labelling of the active progenitor cells in the neurogenic niches, as well as the resting cells throughout the parenchyma. We are characterizing the resting cells and scrutinizing their influence on the brain under different conditions such as during aging. Preliminary experiments have suggested an involvement in the healing processes, which remains to be deciphered, in response to neurodegenerative diseases like multiple sclerosis.

In addition, we aim to activate the quiescent progenitor cell population, either pharmacologically or physically, to induce their proliferation and maturation. A potential approach involves the use of electroconvulsive therapy (ECT), a rapid and highly potent method against severe depression. We and others have reported, that the cell proliferation in the neurogenic niches can be significantly enhanced by ECT. We aim to elucidate whether ECT treatment also influences the activity of quiescent progenitor cells in the brain.

Quiescent progenitor of the cortex expressing the fluorescent transgene (green)